"The US Food and Drug Administration (FDA) has approved Gilead Sciences' fixed-dose HIV combination pill Odefsey containing emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir alafenamide (TAF; 25 mg), the company announced.
The following adverse reactions are discussed in other sections of the labeling:
- Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
- Hematologic toxicity, including neutropenia and anemia [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
- Symptomatic myopathy [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
- Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
- Exacerbations of hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
- Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see WARNINGS AND PRECAUTIONS].
- Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see WARNINGS AND PRECAUTIONS].
- Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS].
- Fat redistribution [see WARNINGS AND PRECAUTIONS].
- Myocardial infarction [see WARNINGS AND PRECAUTIONS].
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Serious and Fatal Abacavir-associated Hypersensitivity Reactions
In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIZIVIR [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.
Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized).
Additional Adverse Reactions with Use of TRIZIVIR
Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 1.
Table 1: Treatment-Emergent (All Causality) Adverse
Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to
5% Frequency) in Therapy-naive Adults (CNA3005) through 48 Weeks of Treatment
|Adverse Reaction||ZIAGEN plus Lamivudine/ Zidovudine
(n = 262)
|Indinavir plus Lamivudine/ Zidovudine
(n = 264)
|Malaise and fatigue||12%||12%|
|Nausea and vomiting||10%||10%|
|Fever and/or chills||6%||3%|
|Viral respiratory infections||5%||5%|
|Renal signs/symptoms||< 1%||5%|
|Pain (non-site-specific)||< 1%||5%|
Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared to none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.
Laboratory abnormalities in CNA3005 are listed in Table 2.
Table 2: Treatment-emergent Laboratory Abnormalities
(Grades 3/4) in CNA3005
|Laboratory Parameter||ZIAGEN plus Lamivudine/ Zidovudine
(n = 262)
|Indinavir plus Lamivudine/ Zidovudine
(n = 264)
|Elevated CPK ( > 4 x ULN)||18 (7%)||18 (7%)|
|ALT ( > 5.0 x ULN)||16 (6%)||16 (6%)|
|Neutropenia ( < 750/mm )||13 (5%)||13 (5%)|
|Hypertriglyceridemia ( > 750 mg/dL)||5 (2%)||3 (1%)|
|Hyperamylasemia ( > 2.0 x ULN)||5 (2%)||1 ( < 1%)|
|Hyperglycemia ( > 13.9 mmol/L)||2 ( < 1%)||2 ( < 1%)|
|Anemia (Hgb ≤ 6.9 g/dL)||0 (0%)||3 (1%)|
|ULN = Upper limit of normal.
n = Number of subjects assessed.
Other Adverse Events
In addition to adverse reactions in Tables 1 and 2, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.
The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiovascular: Myocardial infarction.
Skin: Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see Clinical Trials Experience].
Abacavir, Lamivudine, and/or Zidovudine
Body as a Whole: Redistribution/accumulation of body fat [see WARNINGS AND PRECAUTIONS].
Digestive: Stomatitis. Endocrine and Metabolic: Gynecomastia.
General: Vasculitis, weakness.
Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal: Arthralgia, myalgia, muscle weakness, rhabdomyolysis. Nervous: Dizziness, paresthesia, peripheral neuropathy, seizures.
Read the Trizivir (abacavir sulfate, lamivudine, and zidovudine) Side Effects Center for a complete guide to possible side effects
In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see CLINICAL PHARMACOLOGY]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.
Agents Antagonistic with Zidovudine
Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro:
- Nucleoside analogues e.g., ribavirin
Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
Coadministration with the following drugs may increase the hematologic toxicity of zidovudine:
- Interferon alfa
Read the Trizivir Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 10/23/2015
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